Collagen is the principal structural protein in the body and constitutes approximately one-third of the total body protein. It comprises most of the organic matter of the skin, tendons, bones and teeth and occurs as fibrous inclusions in most other body structures. Some of the properties of collagen are its high tensile strength; its ion exchanging ability, due in part to the binding of electrolytes, metabolites and drugs; its low antigenicity, due to masking of potential antigenic determinants by the helical structure, and its low extensibility, semipermeability, and solubility. Furthermore collagen is a natural substance for cell adhesion. These properties and much more make this protein suitable for fabrication into medical products such as in the manufacture of implantable prostheses, as cell growth substrates, and in the preparation of cellular and acellular tissue equivalents.
Collagen compositions are typically prepared from skin or tendons by dispersion, digestion or dissolution. Dispersion involves mechanically shearing the tissue to produce a suspension of collagen fibers. Digestion involves enzyme degradation of the non-helical telopeptide portions of the collagen molecule, resulting in a solution of atelopeptide collagen. Dissolution involves cleavage of acid labile crosslinks in newly formed collagen fibers resulting in a solution of collagen monomers and polymers. procedures involving acid or enzyme extraction. Enzyme extraction is preferable in many instances because its methodology produces increased yield and higher purity collagen. However enzyme extraction suffers the disadvantage of producing partially degraded collagen, i.e., the extraction enzymes cleave the collagen molecule at the terminal non-helical regions which contain the inter-molecular cross-linkages.
Injectable formulations have been used in the art as tissue bulking compositions, particularly in urology and plastic surgery. U.S. Pat. No. 3,949,073 to Daniels et al discloses an injectable collagen in aqueous form composed of enzyme extracted collagen. The enzyme used in the extraction process is pepsin which yields atelopeptide collagen. The concentration of the final product is up to about 20 mg/mL but insoluble collagen fibrils may also be added to the composition. Upon implantation to a patient, however, the volume persistence of the implant decreases partly due to the absorption of the aqueous carrier by the body and partly due to the low concentration of the collagen. Follow up injections at the site are usually necessary.
Volume persistence and shape persistence desired of the injected collagen implant In the time after injection of collagen compositions known in the art, the volume decreases due to the absorption of liquid component of the composition by the body. Higher concentrations of collagen helps to maintain volume persistence, but at the same time decreases extrudability and intrudability of the composition.
U.S. Pat. No. 4,642,117 to Nguyen et al discloses an injectable collagen material composed of reconstituted, mechanically sheared atelopeptide collagen fibers. The collagen fibers are mechanically sheared using a rigid screen mesh to reduce the size of the larger fibers to about 50-150 microns. The disclosed composition has a final concentration of about 35-65 mg/mL, but it was determined that the extrudability and intrudability are poor. U.S. Pat. No. 4,582,640 to Smestad describes a similar composition that is glutaraldehyde crosslinked. In clinical testing, however, it was found that the intrudability of the composition was also difficult, especially for intradermal injections. U.S. Pat. No. 4,803,075 to Wallace et al discloses a similar injectable compositions with the addition of a biocompatible fluid lubricant to overcome the problems of extrudability and intrudability.
As well as volume persistence, shape persistence is desired of the injectable collagen compositions know in the art. When injected, the collagen tends to migrate through the tissue; therefore, if specific and local tissue augmentation or bulking is required, such migration would necessitate subsequent injections.
The present invention describes a collagen composition in the form of reconstituted collagen fiber segments, methods for making collagen fiber segments and their use as an injectable collagen composition that overcomes the drawbacks of injectable collagen compositions known in the art.